Genetic Factors in the Regulation of Striatal and Extrastriatal Dopamine D2 Receptor Expression

Positron emission tomography (PET) studies on healthy individuals have revealed a marked interindividual variability in striatal dopamine D2 receptor density that can be partly accounted for by genetic factors. The examination of the extrastriatal lowdensity D2 receptor populations has been impeded by the lack of suitable tracers. However, the quantification of these D2 receptor populations is now feasible with recently developed PET radioligands. The objective of this thesis was to study brain neurobiological correlates of common functional genetic variants residing in candidate genes relevant for D2 receptor functioning. For this purpose, healthy subjects were studied with PET imaging using [11C]raclopride and [11C]FLB457 as radioligands. The candidate genes examined in this work were the human D2 receptor gene (DRD2) and the catechol-Omethyltransferase gene (COMT). The region-specific genotypic influences were explored by comparing D2 receptor binding properties in the striatum, the cortex and the thalamus. As an additional study objective, the relationship between cortical D2 receptor density and a cognitive phenotype i.e. verbal memory and learning was assessed. The main finding of this study was that DRD2 C957T genotype altered markedly D2 receptor density in the cortex and the thalamus whereas in the striatum the C957T genotype affected D2 receptor affinity, but not density. Furthermore, the A1 allele of the DRD2-related TaqIA polymorphism showed increased cortical and thalamic D2 receptor density, but had the opposite effect on striatal D2 receptor density. The DRD2 –141C Ins/Del or the COMT Val158Met genotypes did not change D2 receptor binding properties. Finally, unlike previously reported, cortical D2 receptor density did not show any significant correlation with verbal memory function. The results of this study suggest that the C957T and the TaqIA genotypes have region-specific neurobiological correlates in brain dopamine D2 receptor availability in vivo. The biological mechanisms underlying these findings are unclear, but they may be related to the region-specific regulation of dopamine neurotranssion, gene/receptor expression and epigenesis. These findings contribute to the understanding of the genetic regulation of dopamine and D2 receptor-related brain functions in vivo in man. In addition, the results provide potentially useful endophenotypes for genetic research on psychiatric and neurological disorders.Siirretty Doriast

Functional significance of central D1 receptors in cognition: beyond working memory

The role of dopamine D1 receptors in prefrontal cortex function, including working memory, is well acknowledged. However, relatively little is known about their role in other cognitive or emotional functions. We measured both D1 and D2 receptors in the brain using positron emission tomography in healthy subjects, with the aim of elucidating how regional D1 and D2 receptors are differentially involved in cognitive and emotional functions beyond working memory. We found an inverted U-shaped relation between prefrontal D1 receptor availability and Wisconsin Card Sorting Test performance, indicating that too little or too much D1 receptor stimulation impairs working memory or set shifting. In addition, variability of D1 receptor availability in the amygdala and striatum was related to individual differences in emotional responses and decision-making processes, respectively. These observations suggest that the variability of available D1 receptors might be associated with individual differences in brain functions that require phasic dopamine release. An interdisciplinary approach combining molecular imaging of dopamine neurotransmission with cognitive neuroscience and clinical psychiatry will provide new perspectives for understanding the neurobiology of neuropsychiatric disorders such as schizophrenia, addiction and Parkinson's disease, as well as novel therapeutics for cognitive impairments observed in them

Human aging, dopamine, and cognition : molecular and functional imaging of executive functions and implicit learning

Age-related deficits are legion in task switching, updating of information in working memory (WM) and inhibiting irrelevant information, collectively referred to as executive functions. Executive functions are tightly coupled to the dopaminergic system, and marked dopamine (DA) losses are observed across adulthood and aging. Several human molecular imaging studies have sought confirmation for the hypothesis that age-related DA losses are associated with deficits in executive functions in older adults. Study I extends this line of research by investigating the association between caudate DA D1 receptor density and functional network connectivity in younger (20-30 years) and older adults (65-75 years) using positron emission tomography and functional magnetic resonance imaging (fMRI). In line with the notion that striatal DA is a critical modulator in cortico-striato-cortical pathways, caudate D1 receptor density was significantly associated with fronto-parietal connectivity in functional brain networks related to executive functioning, and there were marked age-related reductions in DA D1 binding potential. These results show that age-related losses of caudate D1 receptors may contribute to reduced functional-network integrity in older adults. Study II examined age differences in D1 receptor density in several striatal and cortical regions of interest. On average, D1 receptor densities were reduced by around 20 % for older compared to younger adults. Most interestingly, correlations between striatal and cortical receptor densities were reduced in older compared to younger adults, suggesting that dopaminergic losses in striatum and cortex occur relatively independently. Moreover, reduced correlations between striatal and cortical receptor densities were related to slower cognitive interference resolution in older adults. This pattern suggests that an imbalance in dopaminergic regulation between striatum and cortex may contribute to older adults’ deficits in executive functions. Implicit learning remains relatively spared in older adults despite strong associations to striatal functions and DA. This fact presents a paradox for the hypothesis that age- related DA losses mediate cognitive decline in aging. Study III and IV explore possible compensatory mechanisms, which may contribute to preserved implicit learning among older adults. Study III showed that increases in striatal fMRI activations during implicit sequence learning were accompanied by decreasing activation of the right medial temporal lobe (MTL) in younger adults. Older adults, however, relied on both striatum and right MTL during task performance. This pattern suggests that the MTL is not necessary for implicit learning in younger adults, but serves compensatory purposes in old age. Study IV used a dual-task design during fMRI acquisition in which a secondary task, designed to tax the MTL, was performed concurrent with an implicit sequence-learning task comparable to that used in Study III. Consistent with the interpretation of the data from Study III, the secondary task disrupted learning in older, but not younger adults. Moreover, differential effects of the secondary task on learning in younger and older adults were observed in activation patterns for right MTL. Collectively, the four studies provide novel insights into the mechanisms by which dopaminergic losses in aging contribute to deficits in executive functions, and suggest compensatory processes, which may account for the relative sparing of implicit learning in old age

Extrastriatal D2/3 receptor availability and executive functioning in alcohol use disorder

Introduction: Alcohol use disorder (AUD) is a chronically relapsing disorder and characterized by dysfunctional learning or in other words the continued intake of alcohol despite negative consequences. Cognitive processes of decision-making, information-updating and set- shifting are associated with the prefrontal cortex (PFC) that is involved in these so called executive functions (EF). The dopaminergic (DA) neurotransmitter system plays a significant role in the modulation of reward learning and can be disrupted in AUD. D2/3 receptor (D2/3R) availability in the striatum has been positively associated with performance on laboratory tests that reflect and rely on EF. Also, striatal D2/3R availability is typically lower in detoxified AUD patients than in healthy controls. It has been shown that chronic alcohol consumption can have an effect on extrastriatal D2/3R availability. This is especially of interest in areas connected to prefrontal integrity and EF. However, only a few studies have examined extrastriatal D2/3R availability in AUD and its relation to performance in laboratory measures of EF. We aim to determine this relationship with a focus on group differences between low risk controls (LR), high risk subjects (HR) with a score > 8 in the Alcohol Use Disorder Identification Test (AUDIT) and AUD patients. Methods: We included 58 subjects (19 LR, 19 HR and 20 AUD) who were equally assessed in EF performance. Extrastriatal D2/3R availability was examined with (18F)-Fallypride (FAL) positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI) and brought in relation to performance on common laboratory measures of EF. Results: Differences in extrastriatal non-displaceable binding potential (BPND) for FAL were observed in several regions of interest (ROIs) (bilateral dorsal anterior cingulate cortex (ACC), bilateral rostral ACC, left dorsolateral prefrontal cortex (PFC) and left ventrolateral PFC). Patients presented significantly less BPND in a number of these areas when compared to HR. EF tests amongst the groups differed in a Digit Span Backwards task. AUD showed a significantly better performance when compared to LR. Performance in the Trail-Making Test Part B (TMT-B) showed a trend to be decreased amongst LR compared to HR and AUD. Extrastriatal BPND in several ROIs was negatively correlated with TMT-B performance. Conclusion: Alcohol consumption has an impact on extrastriatal D2/3R availability and can influence DA transmission in subregions of the ACC and the PFC. This study is adding evidence to a growing body of work with heterogeneous results of responses to chronic alcohol consumption and its impact on EF performance.Einleitung: Alkoholabhängigkeit (AUD) ist eine chronische Erkrankung, die im Krankheitsverlauf durch Rückfälle gekennzeichnet ist. Dies wird zum Teil auf dysfunktionales Lernverhalten zurückgeführt, da der Konsum trotz negativer Konsequenzen weitergeführt wird und keine Verhaltensanpassung erfolgt. Dafür wichtige Prozesse wie Entscheidungsfindung, mentale Flexibilität und Anpassungsfähigkeit werden mit dem präfrontalen Kortex (PFC) assoziiert und unter dem Begriff Exekutiv Funktionen (EF) zusammengefasst. Diese können bei AUD geschwächt sein. Der Neurotransmitter Dopamin (DA) spielt eine Rolle bei der Modulation von Lernvorgängen im Gehirn, vor allem im Belohnungslernen. Das DA-System kann bei chronischem Alkohol Konsum stark verändert sein. So korreliert beispielsweise eine höhere D2/3-Rezeptorverfügbarkeit (D2/3R) im Striatum mit besserem Abschneiden in Tests, die EF testen. Die D2/3-Rezeptorverfügbarkeit im Striatum ist bei AUD typischerweise erniedrigt. Es lässt sich also vermuten, dass auch extrastriatale DA- vermittelte Veränderungen bei chronischem Alkoholkonsum eine Rolle spielen. Diese Veränderungen können in Bereichen wie dem PFC auftreten, die für EF wichtig sind. Jedoch haben nur wenige Studien die extrastriatale D2/3-Rezeptorverfügbarkeit in AUD untersucht. Auch die Verbindung zum Abschneiden in EF Tests ist bisher nicht eingehend untersucht worden. In dieser Studie wollen wir eine Assoziation von D2/3-Rezeptorverfügbarkeit und dem Abschneiden in EF Tests überprüfen. Dies geschieht mit einem Fokus auf die Unterscheidung in Kontrollen (LR), Hochrisiko-Konsumenten (HR) mit einem Score > 8 im Alcohol Use Disorder Identification Test (AUDIT) und alkoholabhängige Patienten (AUD). Methoden: Es wurden 58 Subjekte eingeschlossen (19 LR, 19 HR, 20 AUD). Alle Teilnehmenden durchliefen eine Abfolge von neuropsychologischen Tests. Die extrastriatale D2/3-Rezeptorverfügbarkeit wurde mittels (18F)-Fallypride (FAL) Positronen-Emissions-Tomographie/Computertomographie (PET/CT) und Magnetresonanztomographie (MRI) gemessen und mit den experimentellen Messergebnissen in Verbindung gesetzt. Ergebnisse: Das extrastriatale non-displaceable binding potential (BPND) unterscheidet sich im Gruppenvergleich in mehreren ROIs (bilateraler dorsaler anteriorer zingulärer Kortex (ACC) und rostraler ACC; linker dorsolateraler PFC und linker ventrolateraler PFC). Bei Patienten zeigte sich ein signifikant geringeres BPND im Vergleich zu HR. In den EF Tests wurde ein Unterschied im Abschneiden im Digit Span Backwards Test gefunden, wobei Patienten signifikant besser abschnitten als LR. Auch beim Trail-Making Test Part B (TMT-B) konnte ein entsprechender Trend beobachtet werden. Das BPND war in mehreren Regionen negativ mit dem Abschneiden im TMT-B korreliert. Schlussfolgerung: Alkoholkonsum kann einen Einfluss auf die extrastriatale Verfügbarkeit von DA Rezeptoren haben und dopaminerge Signalübermittlung vor allem in den Unterregionen des ACC sowie des PFC beeinflussen. Diese Arbeit fügt weitere Erkenntnisse zu den heterogenen Ergebnissen in diesem Feld hinzu, auch bezüglich der Beziehung zu EF

Striatal and extrastriatal dopamine D2/3 receptors studied with [11C]raclopride and high-resolution PET

The human striatum is a heterogeneous structure representing a major part of the dopamine (DA) system’s basal ganglia input and output. Positron emission tomography (PET) is a powerful tool for imaging DA neurotransmission. However, PET measurements suffer from bias caused by the low spatial resolution, especially when imaging small, D2/3 -rich structures such as the ventral striatum (VST). The brain dedicated high-resolution PET scanner, ECAT HRRT (Siemens Medical Solutions, Knoxville, TN, USA) has superior resolution capabilities than its predecessors. In the quantification of striatal D2/3 binding, the in vivo highly selective D2/3 antagonist [11C] raclopride is recognized as a well-validated tracer. The aim of this thesis was to use a traditional test-retest setting to evaluate the feasibility of utilizing the HRRT scanner for exploring not only small brain regions such as the VST but also low density D2/3 areas such as cortex. It was demonstrated that the measurement of striatal D2/3 binding was very reliable, even when studying small brain structures or prolonging the scanning interval. Furthermore, the cortical test-retest parameters displayed good to moderate reproducibility. For the first time in vivo, it was revealed that there are significant divergent rostrocaudal gradients of [11C]raclopride binding in striatal subregions. These results indicate that high-resolution [11C]raclopride PET is very reliable and its improved sensitivity means that it should be possible to detect the often very subtle changes occurring in DA transmission. Another major advantage is the possibility to measure simultaneously striatal and cortical areas. The divergent gradients of D2/3 binding may have functional significance and the average distribution binding could serve as the basis for a future database. Key words: dopamine, PET, HRRT, [11C]raclopride, striatum, VST, gradients, test-retest.Dopamiini D2/3 reseptorien kuvantaminen korkean resoluution PET kameralla ja [11C]raclopridi merkkiaineella. Aivojen tyvitumakkeisiin kuuluva aivojuovio on keskeinen dopamiiniaineenvaihdunnan kannalta. PET menetelmällä voidaan tutkia dopamiiniaineenvaihduntaa reseptoritasolla, mutta sen heikkous on huono spatiaalinen resoluutio, etenkin tutkittaessa pieniä aivoalueita kuten aivojuovion ventraalista osaa (VST). Tässä väitöskirjatutkimuksessa on käytetty aivotutkimukseen suunniteltua korkean resoluution PET-kameraa (ECAT HRRT, Siemens Medical Solutions, Knoxville, TN, USA) ja D2/3 dopamiinireseptoreihin spesifisesti sitoutuvaa [11C]raclopridi PET-merkkiainetta. Tämän väitöskirjatutkimuksen tarkoituksena on selvittää toistomittauksella HRRT kameran soveltuvuutta pienten (VST) ja toisaalta vähän D2/3 reseptoreita sisältävien (aivojen kuorikerros) aivoalueiden kuvantamiseen. HRRT-kameran käyttökelpoisuus osoittautui erittäin hyväksi pienempien aivoalueiden tutkimisessa eikä luotettavuus kärsinyt vaikka kahden mittauksen välistä intervallia pidennettiin. Kuorikerroksen mittauksen luotettavuus oli myös tyydyttävä/hyvä. Lisäksi ensimmäistä kertaa PET menetelmää käyttäen pystyttiin havaitsemaan erisuuntaisia gradientteja [11C]raclopridin sitoutumisessa D2/3 reseptoreihin. Löydösten perusteella korkean resoluution [11C]raclopridi PET menetelmä on erittäin luotettava ja se mahdollisesti lisää mittauksen sensitiivisyyttä havaita hienovaraisia dopamiiniaineenvaihdunnan muutoksia. [11C]raclopridia voisi tulevaisuudessa mahdollisesti käyttää samanaikaisesti sekä aivojuovion että aivojen kuorikerroksen tutkimiseen, joka toisi lisäinformaatiota dopamiinijärjestestelmän toiminnallisesta järjestäytymisestä aivoissa. Havaituilla erilaisilla gradienteilla [11C]raclopridin sitoutumisessa voi olla funktionaalista merkitystä ja keskimääräistä sitoutumista voitaisiin käyttää myös tietokannan pohjana.Siirretty Doriast

The role of genes, stress, and dopamine in the development of schizophrenia

The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia. Because it was initially based on indirect evidence and findings in patients with established schizophrenia, it was unclear what role dopamine played in the onset of the disorder. However, recent studies in people at risk of schizophrenia have found elevated striatal dopamine synthesis capacity and increased dopamine release to stress. Furthermore, striatal dopamine changes have been linked to altered cortical function during cognitive tasks, in line with preclinical evidence that a circuit involving cortical projections to the striatum and midbrain may underlie the striatal dopamine changes. Other studies have shown that a number of environmental risk factors for schizophrenia, such as social isolation and childhood trauma, also affect presynaptic dopaminergic function. Advances in preclinical work and genetics have begun to unravel the molecular architecture linking dopamine, psychosis, and psychosocial stress. Included among the many genes associated with risk of schizophrenia are the gene encoding the dopamine D2 receptor and those involved in the upstream regulation of dopaminergic synthesis, through glutamatergic and gamma-aminobutyric acidergic pathways. A number of these pathways are also linked to the stress response. We review these new lines of evidence and present a model of how genes and environmental factors may sensitize the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation and the onset of psychosis. Finally, we consider the implications for rational drug development, in particular regionally selective dopaminergic modulation, and the potential of genetic factors to stratify patients

Thinking Outside a Less Intact Box: Thalamic Dopamine D2 Receptor Densities Are Negatively Related to Psychometric Creativity in Healthy Individuals

Several lines of evidence support that dopaminergic neurotransmission plays a role in creative thought and behavior. Here, we investigated the relationship between creative ability and dopamine D2 receptor expression in healthy individuals, with a focus on regions where aberrations in dopaminergic function have previously been associated with psychotic symptoms and a genetic liability to schizophrenia. Scores on divergent thinking tests (Inventiveness battery, Berliner Intelligenz Struktur Test) were correlated with regional D2 receptor densities, as measured by Positron Emission Tomography, and the radioligands [11C]raclopride and [11C]FLB 457. The results show a negative correlation between divergent thinking scores and D2 density in the thalamus, also when controlling for age and general cognitive ability. Hence, the results demonstrate that the D2 receptor system, and specifically thalamic function, is important for creative performance, and may be one crucial link between creativity and psychopathology. We suggest that decreased D2 receptor densities in the thalamus lower thalamic gating thresholds, thus increasing thalamocortical information flow. In healthy individuals, who do not suffer from the detrimental effects of psychiatric disease, this may increase performance on divergent thinking tests. In combination with the cognitive functions of higher order cortical networks, this could constitute a basis for the generative and selective processes that underlie real life creativity

Age-differential relationships among dopamine D1 binding potential, fusiform BOLD signal, and face-recognition performance

Facial recognition ability declines in adult aging, but the neural basis for this decline remains unknown. Cortical areas involved in face recognition exhibit lower dopamine (DA) receptor availability and lower blood-oxygen-level-dependent (BOLD) signal during task performance with advancing adult age. We hypothesized that changes in the relationship between these two neural systems are related to age differences in face-recognition ability. To test this hypothesis, we leveraged positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to measure D1 receptor binding potential (BPND) and BOLD signal during facerecognition performance. Twenty younger and 20 older participants performed a face-recognition task during fMRI scanning. Face recognition accuracy was lower in older than in younger adults, as were D1 BPND and BOLD signal across the brain. Using linear regression, significant relationships between DA and BOLD were found in both age-groups in face-processing regions. Interestingly, although the relationship was positive in younger adults, it was negative in older adults (i.e., as D1 BPND decreased, BOLD signal increased). Ratios of BOLD:D1 BPND were calculated and relationships to face-recognition performance were tested. Multiple linear regression revealed a significant Group BOLD:D1 BPND Ratio interaction. These results suggest that, in the healthy system, synchrony between neurotransmitter (DA) and hemodynamic (BOLD) systems optimizes the level of BOLD activation evoked for a given DA input (i.e., the gain parameter of the DA input-neural activation function), facilitating task performance. In the aged system, however, desynchronization between these brain systems would reduce the gain parameter of this function, adversely impacting task performance and contributing to reduced face recognition in older adults